Seminars in oncology
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Seminars in oncology · Dec 2000
ReviewNew insights into anti-HER-2 receptor monoclonal antibody research.
Abnormalities in the expression, structure, or activity of proto-oncogene products contribute to the development and maintenance of the malignant phenotype. For example, c-erbB-2 encodes the HER-2 receptor (also known as c-erbB-2 or c-neu) that is overexpressed, amplified, or both in a number of human malignancies including breast, ovarian, colon, lung, prostate, and cervical cancers. In addition to deregulation of cell-surface HER receptors, cancer cells often show excessive activation and/or nonattenuation of growth factor--inducible signaling components, as well as their downstream transcription factors. ⋯ Using in vitro models, recent studies have shown that HER-2 overexpression may not be a prerequisite for invasion of breast cancer cells, as HER-2 activation by heregulin, which binds to HER-3 or HER-4 and transphosphorylates HER in noninvasive breast cancer cells, could lead to increased motility, enhanced gelatinolytic activity, and invasion. Furthermore, these ligand-driven phenotypic changes were completely suppressed by trastuzumab, which also blocked interactions between HER-2 and HER-3 receptors in heregulin-treated breast cancer cells, and inhibited the phosphatidylinositol-3' kinase-dependent pathway, but not the mitogen-activated protein kinase pathway. These phenotypic effects of anti-HER-2 monoclonal antibody are of special interest, because they point to potential therapeutic effects of trastuzumab in inhibiting the invasion and metastasis of breast cancer with low receptor expression.
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Seminars in oncology · Dec 2000
ReviewOverview of idiopathic thrombocytopenic purpura: new approach to refractory patients.
Idiopathic thrombocytopenic purpura is a disorder in which autoantibodies are made to platelets, resulting in accelerated platelet destruction. The diagnosis may be made in outpatients who are previously well or in patients with multiple medical conditions and medications. There are no unequivocal ways to distinguish immune thrombocytopenias from other thrombocytopenias, even with state-of-the-art tests including anti-platelet antibodies, thrombopoietin, glycocalicin, and platelet reticulocyte counts. ⋯ Treatment of idiopathic thrombocytopenic purpura should be individualized. Substantial platelet increases are seen in more than 50% of patients who receive intravenous IgG, intravenous anti-D, steroids, or splenectomy. Two additional agents showing promising clinical trial experience are anti-CD40 ligand and rituximab (Rituxan; Genentech, Inc, South San Francisco, CA and IDEC Pharmaceutical Corporation, San Diego, CA).
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Seminars in oncology · Dec 2000
The use of ibritumomab tiuxetan radioimmunotherapy for patients with relapsed B-cell non-Hodgkin's lymphoma.
Rituximab (Rituxan; Genentech, Inc, South San Francisco, CA and IDEC Pharmaceutical Corporation, San Diego, CA) is a monoclonal antibody that targets the CD20 antigen present in most B-cell non-Hodgkin's lymphomas. Previous studies have shown overall response rates (ORR) of approximately 50% in relapsed patients. Ibritumomab is the murine parent anti-CD20 antibody that is linked through a MX-DTPA chelator to yttrium 90 (90Y) to form the radioimmunoconjugate 90Y-ibritumomab tiuxetan (Zevalin; IDEC Pharmaceuticals, San Diego, CA). ⋯ An interim analysis of the first 90 patients showed an ORR of 80% with 90Y-ibritumomab tiuxetan versus 44% with rituximab (P < .05). A subsequent trial for patients with rituximab-refractory disease showed a 46% ORR. These studies show that 90Y-ibritumomab tiuxetan is an active agent in relapsed non-Hodgkin's lymphoma and appears to have a higher ORR compared with unconjugated rituximab.
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Seminars in oncology · Dec 2000
A pilot study of the anti-CD20 monoclonal antibody rituximab in patients with refractory immune thrombocytopenia.
We conducted a prospective pilot phase I/II clinical trial to evaluate the toxicity and response rate of the chimeric anti-CD20 monoclonal antibody, rituximab (Rituxan; Genentech, Inc, South San Francisco, CA, and IDEC Pharmaceutical Corporation, San Diego, CA), in the treatment of patients with immune thrombocytopenic purpura. Patients with a clinical diagnosis of idiopathic thrombocytopenic purpura who had failed corticosteroid therapy and whose platelet count was less than 75,000/microL were eligible for the study. Rituximab was administered in a dose-escalation fashion using doses ranging from 50 to 375 mg/m2 weekly for 4 weeks. ⋯ Three of nine patients (30%) who have received rituximab at doses close or equal to the full dose have shown an objective clinical response (two complete responses, one partial response). The study is currently ongoing, and conclusions regarding the overall response rate, clinical parameters that influence response, surrogate markers of response, and the underlying mechanism of response remain to be addressed. The current study should provide answers to a number of important questions regarding the role of rituximab in the treatment of this and other autoimmune disorders.
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The HER2 gene (also known as neu and as c-erb-B2) encodes a 185-kd transmembrane glycoprotein receptor with intrinsic tyrosine kinase activity. HER2 is overexpressed in 25% to 30% of human breast cancers, plays a role in the pathogenesis of breast cancer, and predicts for a worse prognosis in patients with metastatic disease. Trastuzumab (Herceptin; Genentech, Inc, So. ⋯ The most clinically significant adverse event has been cardiac dysfunction syndrome, which occurred in less than 5% of patients. Trastuzumab is not associated with the other commonly observed side effects of chemotherapy, such as alopecia, mucositis, and neutropenia. The results from these studies demonstrate that trastuzumab is active and safe in patients with metastatic HER2-overexpressing breast cancer.